Format

Send to

Choose Destination
See comment in PubMed Commons below
J Mol Neurosci. 2004;23(3):235-46.

ApoE and Abeta1-42 interactions: effects of isoform and conformation on structure and function.

Author information

1
Department of Medicine, Division of Geriatrics, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201, USA.

Abstract

Abnormalities in the processing of amyloid precursor protein to amyloid-beta (Abeta) are causal factors, and the presence of the epsilon4 allele of apolipoprotein E (apoE) is the primary risk factor for Alzheimer's disease (AD). Based, at least in part, on these genetics, the potential structural and functional interactions between these two proteins are the focus of our research. To understand the nature of the physical interactions between apoE and Abeta, we initially utilized gel-shift assays to demonstrate that native apoE2 and E3 (associated with lipid particles) form an SDS-stable complex with Abeta that is more abundant than the apoE4:Abeta complex. We further demonstrated that exogenous apoE3 but not E4 prevents Abeta-induced neurotoxicity by a process that requires apoE receptors. In addition, both exogenous apoE3 and E4 prevent Abeta-induced, glial-mediated inflammation, also via a process that requires apoE receptors. These functional effects all occur at a molar ratio of apoE to Abeta of 1:30. Because the biological activities for both apoE and Abeta are profoundly influenced by their isoform and conformation, respectively, we further investigated the idea that apoE3 and E4 differentially interact with particular aggregation species of Abeta1-42. Our overall hypothesis is that apoE has two general functions in relation to Abeta. First, apoE interacts with oligomeric Abeta via an apoE receptor-mediated process to inhibit neurotoxicity and neuroinflammation (apoE3 > apoE4) a process possibly related to binding and clearance of apoE3:oligomer complexes. Second, apoE facilitates the deposition of Abeta as amyloid (apoE4 > apoE3). We will continue to investigate the effect of apoE isoform and Abeta conformation on the structural and functional interactions between these two proteins in relation to the pathogenesis of AD.

PMID:
15181252
DOI:
10.1385/JMN:23:3:235
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Springer
    Loading ...
    Support Center